Pharmacology of cardiac potassium channels

Abstract

Cardiac K+ channels are membrane-spanning proteins that allow the passive movement of K+ ions across the cell membrane along its electrochemical gradient. They regulate the resting membrane potential, the frequency of pacemaker cells and the shape and duration of the cardiac action potential. Additionally, they have been recognized as potential targets for the actions of neurotransmitters and hormones and class III antiarrhythmic drugs that prolong the action potential duration (APD) and refractoriness and have been found effective to prevent/suppress cardiac arrhythmias. In the human heart, K+ channels include voltage-gated channels, such as the rapidly activating and inactivating transient outward current (Ito1), the ultrarapid (IKur), rapid (IKr) and slow (IKs) components of the delayed rectifier current and the inward rectifier current (IK1), the ligand-gated channels, including the adenosine triphosphate-sensitive (IKATP) and the acetylcholine-activated (IKAch) currents and the leak channels. Changes in the expression of K+ channels explain the regional variations in the morphology and duration of the cardiac action potential among different cardiac regions and are influenced by heart rate, intracellular signalling pathways, drugs and cardiovascular disorders. A progressive number of cardiac and noncardiac drugs block cardiac K+ channels and can cause a marked prolongation of the action potential duration (i.e. an acquired long QT syndrome, LQTS) and a distinct polymorphic ventricular tachycardia termed torsades de pointes. In addition, mutations in the genes encoding IKr (KCNH2/KCNE2) and IKs (KCNQ1/KCNE1) channels have been identified in some types of the congenital long QT syndrome. This review concentrates on the function, molecular determinants, regulation and, particularly, on the mechanism of action of drugs modulating the K+ channels present in the sarcolemma of human cardiac myocytes that contribute to the different phases of the cardiac action potential under physiological and pathological conditions.

Isoproterenol disperses distribution of NADPH oxidase, MMP-9, and pPKCε in the heart, which are mitigated by endothelin receptor antagonist CPU0213

“…KCNH2 is an important target in arrhythmogenesis and antiarrhythmic activity [33] . An increased current in KCNH2 has been found in SQTS resulting from gain of function mutation, manifesting an increased risk for SCD [34] .…”

Effects of the histamine H1 receptor antagonist hydroxyzine on hERG K+ channels and cardiac action potential duration

“…During phase 2, inward depolarizing currents through Na + and L-type Ca 2+ channels are balanced by the various components of the delayed rectifier K + current, such as I Kur , the rapidly activating delayed rectifier K + current (I Kr ), and the slowly activating delayed rectifier K + current (I Ks ). The terminal phase 3 of repolarization is due to increasing conductance of the channels that carry I Kr , I Ks , and inwardly rectifying K + currents (I Kir ) [2] .…”

Novel Kv7.1-Phosphatidylinositol 4,5-Bisphosphate Interaction Sites Uncovered by Charge Neutralization Scanning

“…The noninactivating K v 7.1/KCNE1 channel complex shows slow activation and deactivation kinetics (1,4,8,9). These channels mediate the slowly activating cardiac potassium current I Ks (1,3), which contributes to the repolarization of myocyte membranes during phase 3 of the cardiac action potential (10,11). Many mutations in K v 7.1-and KCNE1-encoding genes have been reported to result in loss of function and to cause long QT syndrome (LQTS), 2 which is associated with cardiac arrhythmia, syncope, and sudden cardiac death (12)(13)(14)(15)(16)(17)(18).…”